The present invention, in some embodiments thereof, relates to a method of treating ductal carcinoma in situ (DCIS).
The mammary gland grows rapidly at puberty to produce an elaborate tree-like structure composed of an inner layer of luminal cells, which are surrounded by an outer layer of myoepithelial cells. Later cycles of expansion and involution occur during each menstrual cycle and—even more dramatically—with each pregnancy. Mechanisms underlying formation of the lumen of mammary ducts include cell divisions with the metaphase plates organized perpendicular to the apical surface, and luminal apoptosis promoted by disengagement of inner cell layers from the basement membrane. However, the exact mechanisms that regulate duct renewal and apoptosis, as well as their relevance to malignant transformation, remain incompletely understood. In line with diverse mechanisms and cell type heterogeneity, human mammary tumors display marked morphological and molecular diversity. One aggressive subtype, comprising 20-25% of all invasive ductal carcinomas, is characterized by amplification of the HER2 gene, resulting in overexpression of the encoded HER2 oncoprotein (also known as ERBB-2/Neu). Treatment with Trastuzumab, an antibody specific to HER2, has been shown to improve outcomes for women with high-risk, early stage or metastatic breast tumors that overexpress HER2.
Another signal transduction pathway critical for breast cancer progression, comprises Notch family receptors and their membrane-bound ligands. The family includes four conserved transmembrane receptors (Notch1 through Notch4) and five surface-localized ligands (Jagged1, Jagged2, Delta-like1 through Delta-like3), which play fundamental roles in self-renewal and proliferation of progenitor and adult stem cells of the mammary gland. For instance, Notch1 and Notch3 regulate expression of c-Myc and Cyclin D1 to promote cell proliferation. Notch signaling is activated through receptor-ligand interactions between neighboring cells, resulting in successive proteolytic cleavages of Notch proteins by the tumor necrosis factor converting enzyme (TACE; also called ADAM17) and the γ-secretase complex. This releases the Notch intracellular domain (NICD) from the plasma membrane, permitting its translocation into the nucleus and formation of a trimeric transcriptional activator complex with a DNA-binding protein, CSL (also termed CBF-1 and RBP-Jκ), and Mastermind. The complex induces transcription of the HERP and HES gene families, thereby regulating the expression of multiple genes involved in cell growth, differentiation and survival.
Imatani and Callahan 2000, Oncogene 19: 223-231, Stylianou et al 2006, Cancer Res 66: 1517-1525 teach that the survival-promoting activity of the pathway likely underlays the observed ability of Notch family members to promote mammary tumors.
Reedijk et al 2005, Cancer Res 65: 8530-8537 teach that in humans, high co-expression of Notch1 and its ligand, JAG-1, associates with poor overall survival of breast cancer patients.
Osipo et al [Oncogene. 2008 Aug. 28; 27(37):5019-32, 2008] teaches administration of a HER2 inhibitor and a gamma secretase inhibitor for the treatment of breast cancer.
Han et al., [Abstract No. 3028, 2011 ASCO Annual meeting] teaches combination therapy for the treatment of cancer using a HER2 inhibitor (trastuzumab and lapatinib) and an AKT inhibitor (MK2206).